Derivatives of Xanthone Compounds

ABSTRACT

The present invention relates to xanthone analogs. Such compounds may be used in the treatment of bacterial infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Application of U.S. Ser. No.14/343,818, filed Jun. 25, 2014, which is a National Stage applicationunder 35 U.S.C. § 371 of International Application No.PCT/SG2012/000328, having an International Filing Date of Sep. 10, 2012,which claims the benefit of Singapore Application No. 201106479-7 filedSep. 8, 2011.

TECHNICAL FIELD

The present disclosure generally relates to derivatives of xanthonecompounds. The present disclosure also relates to use of derivatives ofxanthone compounds in the treatment of microbial disease.

BACKGROUND

Typically, antibiotic medications are used to treat microbial infectionsin patients. Many diseases that once killed people can now be treatedeffectively with antibiotics. However, some microbial organisms havebecome resistant to commonly used antibiotics.

Antibiotic resistant bacteria are bacteria that are extremely difficultto kill by most antibiotics and often require very high concentrationsor combinations of several antibiotics. They are able to survive andeven multiply in the presence of one or more antibiotic agents. Mostinfection-causing bacteria can become resistant to at least someantibiotics. Bacteria that are resistant to many antibiotics are knownas multi-resistant organisms (MROs) or multi-drug resistant MDRs.

Antibiotic resistance can cause serious, prolonged disease and/or deathand is an important public health problem world-wide. It can beminimised by avoiding unnecessary prescribing and overprescribing ofantibiotics, the correct use of prescribed antibiotics, and good hygieneand infection control.

Some bacteria are naturally resistant to some antibiotics. For example,benzyl penicillin has very little effect on most organisms found in thehuman digestive system (gut). Some bacteria have developed resistance toantibiotics that were once commonly used to treat them. For example,Staphylococcus aureus (‘golden staph’) and Neisseria gonorrhoeae (thecause of gonorrhoea) are now almost always resistant to benzylpenicillin. In the past, these infections were usually controlled bypenicillin.

The most serious concern with antibiotic resistance is that the bacteriahave become resistant to almost all of the easily available antibiotics.Important examples are methicillin-resistant Staphylococcusaureus(MRSA), vancomycin-resistant Enterococcus(VRE) andmulti-drug-resistant Mycobacterium tuberculosis(MDR-TB).

MRSA is currently the most serious hospital-acquired infection and as itdoes not respond to treatments with almost all the known and mostpowerful antibiotics, it has been termed a “superbug” out of humancontrol. In fact, because of the untamed nature of the “superbug”,experts have been predicting that the era of antibiotics is over.

One promising approach to efficiently address MRSA infection is todevelop a new generation of antibiotics by approaches of molecularmimicking of natural antimicrobial peptides (AMPs) and utilising naturalcompounds.

There is a need to provide an alternative antibiotic agent thatovercomes, or at least ameliorates, one or more of the disadvantagesdescribed above.

SUMMARY

According to a first aspect, there is provided a compound of Formula Ior a salt thereof:

whereineach of R¹ and R² are each independently is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —(C═O)R¹¹, —(C═O)OR¹¹,—(C═O)NR¹²R¹³, —SO₂R¹¹, —SO₂NR¹²R¹³, or R¹⁴, wherein R¹⁴ is

whereinn is 0-20;X is —O—, —(C═O)—, —O(C═O)—, —(C═O)O—, —N(R¹¹)—, —(C═O)N(R¹¹)—,—N(R¹¹)(C═O)—, —O(C═O)N(R¹¹)—, —N(R¹¹)(C═O)O—, —N(R¹²)(C═O)N(R¹³)—,—NR¹¹SO₂—, or —SO₂NR¹¹—;each of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²² independently foreach occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkenyl, aralkyl, heteroaryl, heterocycloalkyl,heterocycloalkenyl, halide, cyano, nitro, isocyanate, —R¹⁴, —OR¹¹,—SR¹¹, —(C═O)R¹¹, —(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³,—O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³,—NR¹²(C═O)R¹³, —(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹,—SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²) R¹¹, or—N(R¹³)(C═NR¹²)NR¹²R¹³; or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², or R²³ taken together with the carbon to which they arebonded form (C═O); or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², or R²³ taken together with the carbon to which they are bondedform a 3-8 membered carbocylic or heterocyclic ring; or any twoinstances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³ takentogether form a bond;R²³ independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heteroaryl,heterocycloalkyl, heterocycloalkenyl, halide, cyano, nitro, isocyanate,—R¹⁴, —OR¹¹, —SR¹¹, —(C═O)R¹¹, —(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹,—(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³,—N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³, —(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹,—OPO₂OR¹¹, —PO₂OR¹¹, —SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹,—NR¹¹(C═NR¹²)R¹³, —N(R¹³)(C═NR¹²) NR¹²R¹³,

each of R³ and R¹⁰ independently for each occurrence is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —O(C═O)R¹¹, —O(C═O)OR¹¹,—O(C═O)NR¹²R¹³, —OSO₃R¹¹, or —OPO₂OR¹¹;each of R⁴ and R⁵ independently is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, heteroaralkyl, —OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, or—O(C═O)NR¹²R¹³; or R⁴ and R⁵ taken together with the carbon to whichthey are bonded form (C═O);each of R⁶, R⁷, R⁸, and R⁹ independently for each occurrence ishydrogen; or R⁶ and R⁷ taken together form a bond; or R⁸ and R⁹ takentogether form a bond;R¹¹ independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, or R¹⁴; andeach of R¹² and R¹³ independently for each occurrence is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl,heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroaralkyl, or R¹⁴;or R¹² or R¹³ taken together form a 3-8 membered heterocyclic ring,wherein at least one of R¹ or R² is R¹⁴.

According to a second aspect, there is provided a compound of Formula IIor a salt thereof:

whereinm is 0-10;

Y is O or H₂;

B is OH, OR¹¹, or NR¹¹R²⁴;each of R³ and R¹⁰ independently for each occurrence is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —O(C═O)R¹¹, —O(C═O)OR¹¹,—O(C═O)NR¹²R¹³, —OSO₃R¹¹, or —OPO₂OR¹¹;each of R⁴ and R⁵ is independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, heteroaralkyl, —OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, or—O(C═O)NR¹²R¹³; or R⁴ and R⁵ taken together with the carbon to whichthey are bonded form (C═O);each of R⁶, R⁷, R⁸, and R⁹ independently for each occurrence ishydrogen; or R⁶ and R⁷ taken together form a bond; or R⁸ and R⁹ takentogether form a bond;R¹¹ is independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, or heteroaralkyl; or R¹¹ and R²⁴ takentogether with the nitrogen to which they are attached form a 3-8membered heterocyclic ring; each of R¹² and R¹³ independently for eachoccurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,or heteroaralkyl; or R¹² or R¹³ taken together form a 3-8 memberedheterocyclic ring;

R²⁴ is

whereinn is 0-12;X is —O—, —(C═O)—, —O(C═O)—, —(C═O)O—, —N(R¹¹)—, —(C═O)N(R¹¹)—,—N(R¹¹)(C═O)—, —O(C═O)N(R¹¹)—, —N(R¹¹)(C═O)O—, —N(R¹²)(C═O)N(R¹³)—,—NR¹¹SO₂—, or —SO₂NR¹¹—;each of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²² independently foreach occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aralkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl,halide, cyano, nitro, isocyanate, —R²⁴, —OR¹¹, —SR¹¹, —(C═O)R¹¹,—(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³,—NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³,—(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹, —PO₂OR¹¹, —SO₂NR¹²R¹³,—(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹, —NR¹¹ (C═NR¹²)R¹³, or—N(R¹³)(C═NR¹²)NR¹²R¹³; or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², or R²³ taken together with the carbon to which they arebonded form (C═O);or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³taken together with the carbon to which they are bonded form a 3-8membered carbocylic or heterocyclic ring; or any two instances of R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³ taken together form a bond;and R²³ independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heteroaryl,heterocycloalkyl, heterocycloalkenyl, halide, cyano, nitro, isocyanate,an amino acid, a dipeptide, a tripeptide, an oligopeptide, —R²⁴, —OR¹¹,—SR¹¹, —(C═O)R¹¹, —(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³,—O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³,—NR¹²(C═O)R¹³, —(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹,—PO₂OR¹¹, —SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹, —NR¹¹(C═NR¹²)R¹³, —N(R¹³)(C═NR¹²)NR¹²R¹³,

whereinm is 1-10;each of R³ and R¹⁰ independently for each occurrence is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —O(C═O)R¹¹, —O(C═O)OR¹¹,—(C═O)NR¹²R¹³, —OSO₃R¹¹, or —OPO₂OR¹¹;R⁴ and R⁵ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —OR¹¹, —O(C═O)R¹¹,—O(C═O)OR¹¹, and —O(C═O)NR¹²R¹³; or R⁴ and R⁵ taken together with thecarbon to which they are bonded form (C═O);each of R⁶, R⁷, R⁸, and R⁹ independently for each occurrence ishydrogen; or R⁶ and R⁷ taken together form a bond; or R⁸ and R⁹ takentogether form a bond;R¹¹ is independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl; or R¹¹ and R²⁴ takentogether with the nitrogen to which they are attached form a 3-8membered heterocyclic ring; each of R¹² and R¹³ independently for eachoccurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,or heteroaralkyl; or R¹² or R¹³ taken together form a 3-8 memberedheterocyclic ring;

R²⁴ is

whereinn is 0-12;X is —O—, —(C═O)—, —O(C═O)—, —(C═O)O—, —N(R¹¹)—, —(C═O)N(R¹¹)—,—N(R¹¹)(C═O)—, —O(C═O)N(R¹¹)—, —N(R¹¹)(C═O)O—, —N(R¹²)(C═O)N(R¹³)—,—NR¹¹SO₂—, or —SO₂NR¹¹—;each of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²² independently foreach occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aralkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl,halide, cyano, nitro, isocyanate, —R²⁴, —OR¹¹, —SR¹¹, —(C═O)R¹¹,—(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³,—NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³,—(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹, —PO₂OR¹¹, —SO₂NR¹²R¹³,—(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹, —NR¹¹ (C═NR¹²)R¹³, or—N(R¹³)(C═NR¹²)NR¹²R¹³; or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², or R²³ taken together with the carbon to which they arebonded form (C═O);or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³taken together with the carbon to which they are bonded form a 3-8membered carbocylic or heterocyclic ring; or any two instances of R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³ taken together form a bond;R²³ independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heteroaryl,heterocycloalkyl, heterocycloalkenyl, halide, cyano, nitro, isocyanate,—R¹⁴, —OR¹¹, —SR¹¹, —(C═O)R¹¹, —(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹,—(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³,—N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³, —(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹,—OPO₂OR¹¹, —SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹,

According to a fourth aspect, there is provided a compound of formula:

According to a fifth aspect, there is provided a compound of formula:

According to a sixth aspect, there is provided a composition comprisinga compound as defined herein, together with a carrier.

According to a seventh aspect, there is provided a pharmaceuticalcomposition comprising a compound as defined herein, together with apharmaceutically acceptable carrier.

According to an eighth aspect, there is provided a compound as definedherein, for use as a medicament.

According to a ninth aspect, there is provided use of a compound asdefined herein, in the preparation or manufacture of a medicament forthe treatment of a microbial infection.

According to a tenth aspect, there is provided a pharmaceutical dosageform comprising a compound as defined herein.

According to an eleventh aspect, there is provided a pharmaceuticaldosage form comprising a composition as defined herein.

According to a twelfth aspect, there is provided a kit comprising acompound as defined herein and directions for use.

According to a thirteenth aspect, there is provided a kit comprising acomposition as defined herein and directions for use.

According to a fourteenth aspect, there is provided a kit comprising thepharmaceutical dosage form as defined herein and directions for use.

According to a fifteenth aspect, there is provided a method for treatinga microbial infection comprising the step of administering an effectiveamount of a compound as defined herein or a composition as definedherein to a patient in need of such treatment.

Definitions

The following words and terms used herein shall have the meaningindicated:

The following are some definitions that may be helpful in understandingthe description of the present invention. These are intended as generaldefinitions and should in no way limit the scope of the presentinvention to those terms alone, but are put forth for a betterunderstanding of the following description.

Unless the context requires otherwise or specifically stated to thecontrary, integers, steps, or elements of the invention recited hereinas singular integers, steps or elements clearly encompass both singularand plural forms of the recited integers, steps or elements.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated step or element orinteger or group of steps or elements or integers, but not the exclusionof any other step or element or integer or group of elements orintegers. Thus, in the context of this specification, the term“comprising” means “including principally, but not necessarily solely”.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications. The invention alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations or any two or more of said steps or features.In the context of this specification, the term “amino acid” is definedas having at least one primary, secondary, tertiary or quaternary aminogroup, and at least one acid group, wherein the acid group may be acarboxylic, sulfonic, or phosphonic acid, or mixtures thereof. The aminogroups may be “alpha”, “beta”, “gamma” . . . to “omega” with respect tothe acid group(s). The backbone of the “amino acid” may be substitutedwith one or more groups selected from halogen, hydroxy, guanido,heterocyclic groups. Thus term “amino acids” also includes within itsscope glycine, alanine, valine, leucine, isoleucine, methionine,proline, phenylalanine, tryptophane, serine, threonine, cysteine,tyrosine, asparagine, glutamine, asparte, glutamine, lysine, arginineand histidine, taurine, betaine, N-methylalanine etc. (L) and (D) formsof amino acids are included in the scope of this invention. The term“amino acid” is also intended to encompass unnatural or non-naturalforms of amino acids such as ornithine and derivatives thereof, alaninederivatives, alicyclic amino acids, arginine derivatives, aromatic aminoacids, asparagine derivatives, aspartic acid derivatives, beta-aminoacids, cysteine derivatives, DAB (2,4-diaminobutyric acid, N-methylamino acids, D-amino acids, diamino acids, DAP (2,3-diaminopropionicacid), glutamic acid derivatives, glutamine derivatives glycinederivatives, histidine derivatives, homo-amino acids, isoleucinederivatives, leucine derivatives, linear core amino acids, lysinederivatives, methionine derivatives, N-methyl amino acids, norleucinederivatives, norvaline derivatives, penicillamine derivatives,phenylalanine derivatives, phenylglycine derivatives, prolinederivatives, pyruvic acid derivatives, pyroglutamine derivatives, serinederivatives, threonine derivatives, tryptophan derivatives, tyrosinederivatives and valine derivatives.

The term “oligopeptide” refers to a peptide comprising from 2 to 20amino acids.

As used herein, the term “alkyl group” includes within its meaningmonovalent (“alkyl”) and divalent (“alkylene”) straight chain orbranched chain saturated aliphatic groups having from 1 to 10 carbonatoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For example,the term alkyl includes, but is not limited to, methyl, ethyl, 1-propyl,isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, amyl,1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl,4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl,2-ethylpentyl, 3-ethylpentyl, heptyl, 1-methylhexyl, 2,2-dimethylpentyl,3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl,1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl,1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 5-methylheptyl,1-methylheptyl, octyl, nonyl, decyl, and the like.

The term “alkenyl group” includes within its meaning monovalent(“alkenyl”) and divalent (“alkenylene”) straight or branched chainunsaturated aliphatic hydrocarbon groups having from 2 to 10 carbonatoms, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and having atleast one double bond, of either E, Z, cis or trans stereochemistrywhere applicable, anywhere in the alkyl chain. Examples of alkenylgroups include but are not limited to ethenyl, vinyl, allyl,1-methylvinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butentyl, 1,3-butadienyl,1-pentenyl, 2-pententyl, 3-pentenyl, 4-pentenyl, 1,3-pentadienyl,2,4-pentadienyl, 1,4-pentadienyl, 3-methyl-2-butenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 2-methylpentenyl,1-heptenyl, 2-heptentyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl,and the like.

The term “alkynyl group” as used herein includes within its meaningmonovalent (“alkynyl”) and divalent (“alkynylene”) straight or branchedchain unsaturated aliphatic hydrocarbon groups having from 2 to 10carbon atoms and having at least one triple bond anywhere in the carbonchain. Examples of alkynyl groups include but are not limited toethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 1-methyl-2-butynyl,3-methyl-1-butynyl, 1-pentynyl, 1-hexynyl, methylpentynyl, 1-heptynyl,2-heptynyl, 1-octynyl, 2-octynyl, 1-nonyl, 1-decynyl, and the like.

The term “cycloalkyl” as used herein refers to cyclic saturatedaliphatic groups and includes within its meaning monovalent(“cycloalkyl”), and divalent (“cycloalkylene”), saturated, monocyclic,bicyclic, polycyclic or fused polycyclic hydrocarbon radicals havingfrom 3 to 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbonatoms. Examples of cycloalkyl groups include but are not limited tocyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl,2-methylcyclopentyl, 3-methylcyclopentyl, cyclohexyl, and the like.

The term “heteroalkyl” refers to a straight- or branched-chain alkylgroup having from 2 to 12 atoms in the chain, one or more of which is aheteroatom selected from S, O, and N. Exemplary heteroalkyls includealkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, andthe like.

The term “cycloalkenyl” as used herein, refers to cyclic unsaturatedaliphatic groups and includes within its meaning monovalent(“cycloalkenyl”) and divalent (“cycloalkenylene”), monocyclic, bicyclic,polycyclic or fused polycyclic hydrocarbon radicals having from 3 to 10carbon atoms and having at least one double bond, of either E, Z, cis ortrans stereochemistry where applicable, anywhere in the alkyl chain.Examples of cycloalkenyl groups include but are not limited tocyclopropenyl, cyclopentenyl, cyclohexenyl, and the like.

The term “heterocycloalkyl” as used herein, includes within its meaningmonovalent (“heterocycloalkyl”) and divalent (“heterocycloalkylene”),saturated, monocyclic, bicyclic, polycyclic or fused hydrocarbonradicals having from 3 to 10 ring atoms wherein 1 to 5 ring atoms areheteroatoms selected from O, N, NH, or S. Examples include azetidinyl,oxiranyl, cyclohexylimino, imdazolidinyl, imidazolinyl, morpholinyl,piperazinyl, piperidinyl, pyridyl, pyrazolidinyl, pyrazolinyl,pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, and the like.

The term “heterocycloalkenyl” as used herein, includes within itsmeaning monovalent (“heterocycloalkenyl”) and divalent(“heterocycloalkenylene”), saturated, monocyclic, bicyclic, polycyclicor fused polycyclic hydrocarbon radicals having from 3 to 10 ring atomsand having at least 1 double bond, wherein from 1 to 5 ring atoms areheteroatoms selected from O, N, NH or S.

The term “heteroaromatic group” and variants such as “heteroaryl” or“heteroarylene” as used herein, includes within its meaning monovalent(“heteroaryl”) and divalent (“heteroarylene”), single, polynuclear,conjugated and fused aromatic radicals having 6 to 20 atoms wherein 1 to6 atoms are heteroatoms selected from O, N, NH and S. Examples of suchgroups include benzimidazolyl, benzisoxazolyl, benzofuranyl,benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl,benzotriazolyl, benzoxazolyl, furanyl, furazanyl, furyl, imidazolyl,indazolyl, indolizinyl, indolinyl, indolyl, isobenzofuranyl, isoindolyl,isothiazolyl, isoxazolyl, oxazolyl, phenanthrolinyl, purinyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridinyl, 2,2′-pyridinyl, pyrimidinyl,pyrrolyl, quinolinyl, quinolyl, thiadiazolyl, thiazolyl, thiophenyl,triazolyl, and the like.

The term “halogen” or variants such as “halide” or “halo” as used hereinrefers to fluorine, chlorine, bromine and iodine.

The term “heteroatom” or variants such as “hetero-” as used hereinrefers to O, N, NH and S.

The term “alkoxy” as used herein refers to straight chain or branchedalkyloxy groups. Examples include methoxy, ethoxy, n-propoxy,isopropoxy, tert-butoxy, and the like.

The term “amino” as used herein refers to groups of the form—NR_(a)R_(b) wherein R_(a) and R_(b) are individually selected from thegroup including but not limited to hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,and optionally substituted aryl groups.

The term “aromatic group”, or variants such as “aryl” or “arylene” asused herein refers to monovalent (“aryl”) and divalent (“arylene”)single, polynuclear, conjugated and fused residues of aromatichydrocarbons having from 6 to 10 carbon atoms. Examples of such groupsinclude phenyl, biphenyl, naphthyl, phenanthrenyl, and the like.

The term “aralkyl” as used herein, includes within its meaningmonovalent (“aryl”) and divalent (“arylene”), single, polynuclear,conjugated and fused aromatic hydrocarbon radicals attached to divalent,saturated, straight and branched chain alkylene radicals.

The term “heteroaralkyl” as used herein, includes within its meaningmonovalent (“heteroaryl”) and divalent (“heteroarylene”), single,polynuclear, conjugated and fused aromatic hydrocarbon radicals attachedto divalent saturated, straight and branched chain alkylene radicals.

The term “optionally substituted” as used herein means the group towhich this term refers may be unsubstituted, or may be substituted withone or more groups independently selected from alkyl, alkenyl, alkynyl,thioalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, halo, carboxyl,haloalkyl, haloalkynyl, hydroxyl, alkoxy, thioalkoxy, alkenyloxy,haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl,nitroalkynyl, nitroheterocyclyl, alkylamino, dialkylamino, alkenylamine,alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy,alkylsulfonyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl,alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio,phosphorus-containing groups such as phosphono and phosphinyl, aryl,heteroaryl, alkylaryl, alkylheteroaryl, cyano, cyanate, isocyanate,—C(O)NH(alkyl), and —C(O)N(alkyl)₂.

The term “haloalkyl” refers to a straight- or branched-chain alkenylgroup having from 2-12 carbon atoms in the chain and where one or morehydrogens is substituted with a halogen. Illustrative haloalkyl groupsinclude trifluoromethyl, 2-bromopropyl, 3-chlorohexyl, 1-iodo-isobutyl,and the like.

The present invention includes within its scope all isomeric forms ofthe compounds disclosed herein, including all diastereomeric isomers,racemates and enantiomers. Thus, formulae (I) and (II) should beunderstood to include, for example, E, Z, cis, trans, (R), (S), (L),(D), (+), and/or (−) forms of the compounds, as appropriate in eachcase.

In the context of this invention the term “administering” and variationsof that term including “administer” and “administration”, includescontacting, applying, delivering or providing a compound or compositionof the invention to an organism, or a surface by any appropriate means.

In the context of this specification, the term “patient” includes humansand individuals of any species of social, economic or researchimportance including but not limited to members of the genus ovine,bovine, equine, porcine, feline, canine, primates (including human andnon-human primates), rodents, murine, caprine, leporine, and avian.

The term “substituted” is intended to indicate that one or more (e.g.,1, 2, 3, 4, or 5; in some embodiments 1, 2, or 3; and in otherembodiments 1 or 2) hydrogen atoms on the group indicated in theexpression using “substituted” is replaced with a selection from theindicated organic or inorganic group(s), or with a suitable organic orinorganic group known to those of skill in the art, provided that theindicated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. Suitable indicated organic orinorganic groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, halo,haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle,cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino,trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl,trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylsilyl, and cyano. Additionally, thesuitable indicated groups can include, e.g., —X, —R, —O—, —OR, —SR, —S—,—NR2, —NR3, ═NR, —CX3, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO2, ═N2,—N3, NC(═O)R, —C(═O)R, —C(═O)NRR—S(═O)2 O—, —S(═O)2 OH, —S(═O)2R,—OS(═O)2 OR, —S(═O)2 NR, —S(═O)R, —OP(═O)O2 RR, —P(═O)O2 RR—P(═O)(O-)2,—P(═O)(OH) 2, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR, —C(O)O—, —C(S)OR,—C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, —C(NR)NRR, where each X isindependently a halogen (or “halo” group): F, Cl, Br, or I; and each Ris independently H, alkyl, aryl, heterocycle, protecting group orprodrug moiety. As would be readily understood by one skilled in theart, when a substituent is keto (i.e., ═O) or thioxo (i.e., ═S), or thelike, then two hydrogen atoms on the substituted atom are replaced.

In the context of this specification, the term “treatment”, refers toany and all uses which remedy a disease state or symptoms, prevent theestablishment of disease, or otherwise prevent, hinder, retard, orreverse the progression of disease or other undesirable symptoms in anyway whatsoever.

In the context of this disclosure the term “administering” andvariations of that term including “administer” and “administration”,includes contacting, applying, delivering or providing a compound orcomposition of the invention to an organism, or a surface by anyappropriate means.

In the context of this disclosure, the term “patient” includes humansand individuals of any species of social, economic or researchimportance including but not limited to members of the type ovine,bovine, equine, porcine, feline, canine, primates (including human andnon-human primates), rodents, murine, caprine, leporine, and avian.

In the context of this disclosure, the term “treatment”, refers to anyand all uses which remedy a disease state or symptoms, prevent theestablishment of disease, or otherwise prevent, hinder, retard, orreverse the progression of disease or other undesirable symptoms in anyway whatsoever.

“Dosage unit form” as used herein refers to physically discrete unitssuited as unitary dosages for the individual to be treated; each unitcontaining a predetermined quantity of compound(s) is calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The compound(s) may be formulated for convenientand effective administration in effective amounts with a suitablepharmaceutically acceptable carrier in an acceptable dosage unit. In thecase of compositions containing supplementary active ingredients, thedosages are determined by reference to the usual dose and manner ofadministration of the said ingredients.

In the context of this disclosure the term “therapeutically effectiveamount”, include meaning a sufficient but non-toxic amount of a compoundor composition of the invention to provide the desired therapeutic ordiagnostic effect. The exact amount required will vary from subject tosubject depending on factors such as the species being treated, the ageand general condition of the subject, the severity of the conditionbeing treated, the particular agent being administered, the mode ofadministration, and so forth. Thus, it is not possible to specify anexact “effective amount”. However, for any given case, an appropriate“effective amount” may be determined by one of ordinary skill in the artusing only routine experimentation.

The language “pharmaceutically acceptable carrier” is intended toinclude solvents, dispersion media, coatings, anti-bacterial andanti-fungal agents, isotonic and absorption delaying agents, and thelike. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the compound, use thereof in thetherapeutic compositions and methods of treatment and prophylaxis iscontemplated.

“Unit dose form” or “dosage form” or “dosage unit form” as used hereinrefers to physically discrete units suited as unitary dosages for theindividual to be treated; each unit containing a predetermined quantityof compound(s) is calculated to produce the desired therapeutic effectin association with the required pharmaceutical carrier. The compound(s)may be formulated for convenient and effective administration ineffective amounts with a suitable pharmaceutically acceptable carrier inan acceptable dosage unit. In the case of compositions containingsupplementary active ingredients, the dosages are determined byreference to the usual dose and manner of administration of the saidingredients.

By “pharmaceutically acceptable salt” it is meant those salts which,within the scope of sound medical judgement, are suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

The word “substantially” does not exclude “completely” e.g. acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the invention.

Unless specified otherwise, the terms “comprising” and “comprise”, andgrammatical variants thereof, are intended to represent “open” or“inclusive” language such that they include recited elements but alsopermit inclusion of additional, unrecited elements.

As used herein, the term “about”, in the context of concentrations ofcomponents of the formulations, typically means+/−5% of the statedvalue, more typically +/−4% of the stated value, more typically +/−3% ofthe stated value, more typically, +/−2% of the stated value, even moretypically +/−1% of the stated value, and even more typically +/−0.5% ofthe stated value.

Throughout this disclosure, certain embodiments may be disclosed in arange format. It should be understood that the description in rangeformat is merely for convenience and brevity and should not be construedas an inflexible limitation on the scope of the disclosed ranges.Accordingly, the description of a range should be considered to havespecifically disclosed all the possible sub-ranges as well as individualnumerical values within that range. For example, description of a rangesuch as from 1 to 6 should be considered to have specifically disclosedsub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4,from 2 to 6, from 3 to 6 etc., as well as individual numbers within thatrange, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of thebreadth of the range.

Certain embodiments may also be described broadly and genericallyherein. Each of the narrower species and subgeneric groupings fallingwithin the generic disclosure also form part of the disclosure. Thisincludes the generic description of the embodiments with a proviso ornegative limitation removing any subject matter from the genus,regardless of whether or not the excised material is specificallyrecited herein.

Disclosure of Optional Embodiments

Exemplary, non-limiting embodiments of compounds provided herein willnow be disclosed.

In one embodiment, the compound or salt thereof is of the followingformula:

whereineach of R¹ and R² are each independently is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —(C═O)R¹¹, —(C═O)OR¹¹,—(C═O)NR¹²R¹³, —SO₂R¹¹, —SO₂NR¹²R¹³, or R¹⁴, wherein R¹⁴ is

whereinn is 0-20;X is —O—, —(C═O)—, —O(C═O)—, —(C═O)O—, —N(R¹¹)—, —(C═O)N(R¹¹)—,—N(R¹¹)(C═O)—, —O(C═O)N(R¹¹)—, —N(R¹¹)(C═O)O—, —N(R¹²)(C═O)N(R¹³)—,—NR¹¹SO₂—, or —SO₂NR¹¹—;each of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²² independently foreach occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkenyl, aralkyl, heteroaryl, heterocycloalkyl,heterocycloalkenyl, halide, cyano, nitro, isocyanate, —R¹⁴, —OR¹¹—,—SR¹¹, —(C═O)R¹¹—, —(C═O)OR¹¹, —O(C═O)R¹¹—, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³,—O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³,—NR¹²(C═O)R¹³, —(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹,—SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹, or—N(R¹³)(C═NR¹²)NR¹²R¹³; or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², or R²³ taken together with the carbon to which they arebonded form (C═O); or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², or R²³ taken together with the carbon to which they are bondedform a 3-8 membered carbocylic or heterocyclic ring; or any twoinstances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³ takentogether form a bond; R²³ independently for each occurrence is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heteroaryl,heterocycloalkyl, heterocycloalkenyl, halide, cyano, nitro, isocyanate,—R¹⁴, —OR¹¹, —SR¹¹, —(C═O)R¹¹, —(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹,—(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³,—N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³, —(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹,—OPO₂OR¹¹, —PO₂OR¹¹, —SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹,—NR¹¹(C═NR¹²)R¹³, —N(R¹³)(C═NR¹²)NR¹²R¹³,

each of R³ and R¹⁰ independently for each occurrence is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —O(C═O)R¹¹, —O(C═O)OR¹¹,—O(C═O)NR¹²R¹³, —OSO₃R¹¹, or —OPO₂OR¹¹;each of R⁴ and R⁵ independently is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, heteroaralkyl, —OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, or—O(C═O)NR¹²R¹³; or R⁴ and R⁵ taken together with the carbon to whichthey are bonded form (C═O);each of R⁶, R⁷, R⁸, and R⁹ independently for each occurrence ishydrogen; or R⁶ and R⁷ taken together form a bond; or R⁸ and R⁹ takentogether form a bond;R¹¹ independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, or R¹⁴; andeach of R¹² and R¹³ independently for each occurrence is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl,heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroaralkyl, or R¹⁴;or R¹² or R¹³ taken together form a 3-8 membered heterocyclic ring,wherein at least one of R¹ or R² is R¹⁴.

In certain embodiments, R¹⁴ is —(CH₂)_(n)R²⁴ and n is 1-20. In certainembodiments, n is 2-12, 2-10, 2-8, 2-6, or 2-4.

In certain embodiments, R¹⁰ is alkyl.

In certain embodiments, R⁴ and R⁵ taken together with the carbon towhich they are bonded form (C═O).

In certain embodiments, R⁶ and R⁷ taken together form a bond and R⁸ andR⁹ taken together form a bond.

In certain embodiments, each of R¹ and R² is R¹⁴.

In certain embodiments, each of R¹ and R² is (CH₂)_(n)R²³ and R²³independently for each occurrence is heteroaryl, heterocycloalkyl,heterocycloalkenyl, halide, —OR¹¹, —SR¹¹, —(C═O)R¹¹, —(C═O)OR¹¹,—O(C═O)R¹¹, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³,—NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³, —(S═O)R¹¹,—SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹, —SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³,—NR¹³(C═NR¹²)R¹¹, or —N(R¹³)(C═NR¹²)NR¹²R¹³.

In certain embodiments, R²³ is selected from the group consisting of

and bromide.

In one embodiment the compound or salt thereof is of the followingformula:

whereinm is 0-10;

Y is O or H₂;

B is OH, OR¹¹, or NR¹¹R²⁴;each of R³ and R¹⁰ independently for each occurrence is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —O(C═O)R¹¹, —O(C═O)OR¹¹,—O(C═O)NR¹²R¹³, —OSO₃R¹¹, or —OPO₂OR¹¹;each of R⁴ and R⁵ is independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, heteroaralkyl, —OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, or—O(C═O)NR¹²R¹³; or R⁴ and R⁵ taken together with the carbon to whichthey are bonded form (C═O);each of R⁶, R⁷, R⁸, and R⁹ independently for each occurrence ishydrogen; or R⁶ and R⁷ taken together form a bond; or R⁸ and R⁹ takentogether form a bond;R¹¹ is independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, or heteroaralkyl; or R¹¹ and R²⁴ takentogether with the nitrogen to which they are attached form a 3-8membered heterocyclic ring; each of R¹² and R¹³ independently for eachoccurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,or heteroaralkyl; or R¹² or R¹³ taken together form a 3-8 memberedheterocyclic ring;

R²⁴ is

whereinn is 0-12;X is —O—, —(C═O)—, —O(C═O)—, —(C═O)O—, —N(R¹¹)—, —(C═O)N(R¹¹)—,—N(R¹¹)(C═O)—, —O(C═O)N(R¹¹)—, —N(R¹¹)(C═O)O—, —N(R¹²)(C═O)N(R¹³)—,—NR¹¹SO₂—, or —SO₂NR¹¹—;each of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²² independently foreach occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aralkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl,halide, cyano, nitro, isocyanate, —R²⁴, —OR¹¹, —SR¹¹, —(C═O)R¹¹,—(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³,—NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³,—(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹, —PO₂OR¹¹, —SO₂NR¹²R¹³,—(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹, —NR¹¹ (C═NR¹²)R¹³, or—N(R¹³)(C═NR¹²)NR¹²R¹³; or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², or R²³ taken together with the carbon to which they arebonded form (C═O);or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³taken together with the carbon to which they are bonded form a 3-8membered carbocylic or heterocyclic ring; or any two instances of R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³ taken together form a bond;and R²³ independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heteroaryl,heterocycloalkyl, heterocycloalkenyl, halide, cyano, nitro, isocyanate,an amino acid, a dipeptide, a tripeptide, an oligopeptide, —R²⁴, —OR¹¹,—SR¹¹, —(C═O)R, —(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³,—O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³,—NR¹²(C═O)R¹³, —(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹,—PO₂OR¹¹, —SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹, —NR¹¹(C═NR¹²)R¹³, —N(R¹³)(C═NR¹²)NR¹²R¹³,

In certain embodiments, R¹⁰ is alkyl.

In certain embodiments, R⁴ and R⁵ taken together with the carbon towhich they are bonded form (C═O).

In certain embodiments, R⁶ and R⁷ taken together form a bond and R⁸ andR⁹ taken together form a bond.

In certain embodiments, M is 1; B is NHR²⁴, and R²⁴ is selected from thegroup consisting of

In one embodiment the compound or salt thereof is of the followingformula:

whereinm is 1-10;each of R³ and R¹⁰ independently for each occurrence is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —O(C═O)R¹¹, —O(C═O)OR¹¹,—(C═O)NR¹²R¹³, —OSO₃R¹¹, or —OPO₂OR¹¹;R⁴ and R⁵ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl, —OR¹¹, —O(C═O)R¹¹,—O(C═O)OR¹¹, and —O(C═O)NR¹²R¹³; or R⁴ and R⁵ taken together with thecarbon to which they are bonded form (C═O);each of R⁶, R⁷, R⁸, and R⁹ independently for each occurrence ishydrogen; or R⁶ and R⁷ taken together form a bond; or R⁸ and R⁹ takentogether form a bond;R¹¹ is independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroaralkyl; or R¹¹ and R²⁴ takentogether with the nitrogen to which they are attached form a 3-8membered heterocyclic ring; each of R¹² and R¹³ independently for eachoccurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,or heteroaralkyl; or R¹² or R¹³ taken together form a 3-8 memberedheterocyclic ring;

R²⁴ is

whereinn is 0-12;X is —O—, —(C═O)—, —O(C═O)—, —(C═O)O—, —N(R¹¹)—, —(C═O)N(R¹¹)—,—N(R¹¹)(C═O)—, —O(C═O)N(R¹¹)—, —N(R¹¹)(C═O)O—, —N(R¹²)(C═O)N(R¹³)—,—NR¹¹SO₂—, or —SO₂NR¹¹—;each of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²² independently foreach occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aralkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl,halide, cyano, nitro, isocyanate, —R²⁴, —OR¹¹, —SR¹¹, —(C═O)R¹¹,—(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹, —(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³,—NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³, —N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³,—(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹, —OPO₂OR¹¹, —PO₂OR¹¹, —SO₂NR¹²R¹³,—(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹, —NR¹¹ (C═NR¹²)R¹³, or—N(R¹³)(C═NR¹²)NR¹²R¹³; or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², or R²³ taken together with the carbon to which they arebonded form (C═O);or any two instances of R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³taken together with the carbon to which they are bonded form a 3-8membered carbocylic or heterocyclic ring; or any two instances of R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², or R²³ taken together form a bond;R²³ independently for each occurrence is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aralkyl, heteroaryl,heterocycloalkyl, heterocycloalkenyl, halide, cyano, nitro, isocyanate,—R¹⁴, —OR¹¹, —SR¹¹, —(C═O)R¹¹, —(C═O)OR¹¹, —O(C═O)R¹¹, —O(C═O)OR¹¹,—(C═O)NR¹²R¹³, —O(C═O)NR¹²R¹³, —NR¹²(C═O)OR¹³, —NR¹²R¹³, —N(R¹²)₂R¹³,—N(R¹²)—NR¹²R¹³, —NR¹²(C═O)R¹³, —(S═O)R¹¹, —SO₂R¹¹, —SO₃R¹¹, —OSO₃R¹¹,—OPO₂OR¹¹, —SO₂NR¹²R¹³, —(C═NR¹²)NR¹²R¹³, —NR¹³(C═NR¹²)R¹¹,

In certain embodiments, R¹⁰ is alkyl.

In certain embodiments, R⁴ and R⁵ taken together with the carbon towhich they are bonded form (C═O).

In certain embodiments, R⁶ and R⁷ taken together form a bond and R⁸ andR⁹ taken together form a bond.

In certain embodiments, R²⁴ is

In one embodiment, the compound or salt thereof is of the followingformula:

whereinn, m and p are each independently an integer from 0 to 20; andR₁, R₂ and R₃ are each independently selected from the group consistingof Hydrogen, alkyl, alkenyl, alkynyl, thioalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, halo, carboxyl, haloalkyl, haloalkynyl,hydroxyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy,nitro, amino, amino acid, a non-natural amino acid, an oligopeptide,guanidine, morpholino, triazole, nitroalkyl, nitroalkenyl, nitroalkynyl,nitroheterocyclyl, alkylamino, dialkylamino, alkenylamine, alkynylamino,acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy,alkylsulfonyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl,alkylsulfenyl, alkylcarbonyloxy, keto, thioxo, alkylthio, acylthio,aryl, heteroaryl, alkylaryl, alkylheteroaryl, cyano, cyanate,isocyanate, —C(O)NH(alkyl), —C(O) N (alkyl)₂, —COOH, —SO₃H —PO₄H₂,polyethylene glycol and sulphonamide.

In certain embodiments, is the compound is selected from the groupconsisting of:

In another embodiment, the compound has the formula:

In another embodiment, the compound has the formula:

In one embodiment, the compound may be a guanidine modifiedalpha-mangostin or a salt thereof represented by the followingstructure.

In one embodiment, the guanidine modified alpha-mangostin may beprepared according to the following reaction scheme:

another embodiment the guanidine modified alpha-mangostin or a saltthereof may be selected from the group consisting of the following:

In another embodiment, the compound as described herein may be asaturated or unsaturated nitrogen heterocycle modified alpha-mangostincompound.

In one embodiment, the saturated or unsaturated nitrogen heterocyclecompound may be a morpholine modified alpha-mangostin compound asfollows:

In another embodiment, the saturated or unsaturated nitrogen heterocyclecompound may be a 1,2,4-triazole modified alpha-mangostin compound asfollows:

In one embodiment, the saturated or unsaturated nitrogen heterocyclecompound may be a pyrrolidine modified alpha-mangostin compound asfollows:

In one embodiment, the compound may be modified with one or more anionicfunctional groups, for example mono, di, tri or more substituted.

In another embodiment the modifications may also include differentlengths of hydrophobic and hydrophilic linkers.

In one embodiment, the compound as described herein may be modified atone or more of A, B, C, D, E, F, as shown in the following structure:

Suitable anionic functional groups may include but are not limited totriazoles, —CO₂H, —SO₃H —OSO₃H —PO₃H₂, and —OPO₃H₂.

In one embodiment, the compound as described herein may be selected fromthe group consisting of:

In another embodiment, the compound may be selected from the groupconsisting of:

In another embodiment, the compound may have the following structure:

wherein n, m and p are each independently selected from an integer from0-20.

In another embodiment, the compound may have the following structure:

wherein n, m and p are each independently selected from an integer from0-20.

In one embodiment, the compound may be a neutral modifiedalpha-mangostin. Suitable neutral modifications may include but are notlimited to halogen, alkyl, sulfonamide or polyethylene glycols (PEG). Inone embodiment, the compound may have the following structure:

wherein:n is an integer of from 0-20R is as previously defined for R₁, R₂ and R₃ described herein.

In one embodiment, the compound may be a bromo-modified alpha-mangostinhaving the following structure:

In one embodiment, the bromo-modified alpha-mangostin may be synthesisedby the following reaction scheme:

one embodiment, the compound as described herein may have the followingstructure:

wherein, n is an integer from 2-20.

In another embodiment, the compound as described herein may have thefollowing structure:

In another embodiment, one compound as described herein may have thefollowing structure:

In another embodiment, the compound as described herein may be asulfonamide modified alpha-mangostin. In one embodiment the sulfonamidemodified alpha-mangostin may have the following structure:

In one embodiment, the sulfonamide modified alpha-mangostin may besynthesised by the following reaction scheme:

In another embodiment, the compound as described herein may be analpha-mangostin peptoid or salt thereof. The alpha-mangostin moleculemay be modified with one or more natural (coded) or unnatural (uncoded)amino acids. Advantageously this modification may impart both apeptide-like structure and peptide-like properties to thealpha-mangostin molecule.

In one embodiment, the alpha-mangostin peptoid may have the followinggeneral structure:

wherein n is an integer of from 0-20;

R may be a basic amino acid group, an acidic amino acid group, a neutralamino acid group, an unnatural amino group or an oligopeptide.

In one embodiment, the natural amino acid is arginine, lysine orhistidine. In another embodiment, the acidic amino acid is aspartic acidor glutamic acid. In another embodiment, the neutral amino acidcomprises a nucleophilic, hydrophobic, aromatic or amide group. Forexample, glycine, alanine, serine, threonine, cysteine, valine, leucine,isoleucine, methionine, proline, phenylalanine, tyrosine, tryptophan,asparagine or glutamine. In another embodiment, the unnatural amino acidmay be ornithine. In another embodiment the oligopeptide comprises 2-8amino acid residues.

In one embodiment, the alpha mangostin peptoid may be synthesisedaccording to the following reaction scheme:

In one embodiment, the alpha-mangostin peptoid has the followingstructure:

In one embodiment, the alpha-mangostin peptoid has the followingstructure:

In one embodiment, the alpha-mangostin peptoid has the followingstructure:

In another embodiment, the alpha-mangostin peptoid has the followingstructure:

In one embodiment, the alpha-mangostin peptoid has the followingstructure:

In one embodiment, the alpha-mangostin peptoid has the followingstructure:

In one embodiment, the alpha-mangostin peptoid has the followingstructure:

In one embodiment, the alpha-mangostin peptoid has the followingstructure:

In another embodiment there is provided a composition comprising acompound as described herein, together with a carrier.

In another embodiment there is provided a pharmaceutical compositioncomprising a compound as described herein, together with apharmaceutically acceptable carrier.

In another embodiment there is provided a compound or composition asdescribed herein, for use as a medicament.

In accordance with the present disclosure, when used for the treatmentor prevention of a microbial infection, compound(s) of the disclosuremay be administered alone. Alternatively, the compounds may beadministered as a pharmaceutical, veterinarial, agricultural, orindustrial formulation which comprises at least one compound accordingto the disclosure. The compound(s) may also be present as suitablesalts, including pharmaceutically acceptable salts.

In accordance with the present disclosure, the compounds of thedisclosure may be used in combination with other known treatments orantimicrobial agents, including antifungal treatments, antibiotics,disinfectants, and the like. Suitable agents are listed, for example, inthe Merck Index, An Encyclopoedia of Chemicals, Drugs and Biologicals,12^(th) Ed., 1996.

Combinations of active agents, including compounds of the disclosure,may be synergistic.

The administration of the compound or composition as described hereinwith another active agent may be done simultaneously, sequentially orseparately.

Suitable pharmaceutically acceptable salts of compounds according to thepresent disclosure may be prepared by mixing a pharmaceuticallyacceptable acid such as hydrochloric acid, sulfuric acid,methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoicacid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaricacid, or citric acid with the compounds of the invention. Suitablepharmaceutically acceptable salts of the compounds of the presentinvention therefore include acid addition salts.

Representative acid addition salts include acetate, adipate, alginate,ascorbate, asparate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, digluconate,cyclopentanepropionate, dodecylsulfate, ethanesulfonate, fumarate,glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate,hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oleate, oxalate, palmitate, pamoate, pectinate, persulfate,3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate,succinate, sulfate, tartrate, thiocyanate, toluenesulfonate,undecanoate, valerate salts, and the like. Representative alkali oralkaline earth metal salts include sodium, lithium potassium, calcium,magnesium, and the like, as well as non-toxic ammonium, quaternaryammonium, and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, triethanolamine and the like.

Convenient modes of administration include injection (subcutaneous,intravenous, and the like), oral administration, inhalation, transdermalapplication, topical creams or gels or powders or eyedrops or topicalcosmetic products, or rectal administration.

Depending on the route of administration, the formulation and/orcompound may be coated with a material to protect the compound from theaction of enzymes, acids and other natural conditions which mayinactivate the therapeutic activity of the compound. The compound mayalso be administered parenterally or intraperitoneally.

Dispersions of the compounds according to the invention may also beprepared in water (as an aqueous dispersion), glycerol, liquidpolyethylene glycols, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, pharmaceutical preparations may contain apreservative to prevent the growth of microorganisms. Pharmaceuticalcompositions suitable for injection include sterile aqueous solutions(where water soluble) or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. Ideally, the composition is stable under the conditions ofmanufacture and storage and may include a preservative to stabilise thecomposition against the contaminating action of microorganisms such asbacteria and fungi.

In one embodiment of the disclosure, the compound(s) of the disclosuremay be administered orally, for example, with an inert diluent or anassimilable edible carrier. The compound(s) and other ingredients mayalso be enclosed in a hard or soft shell gelatin capsule, compressedinto tablets, or incorporated directly into an individual's diet. Fororal therapeutic administration, the compound(s) may be incorporatedwith excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like.

Suitably, such compositions and preparations may contain at least 1% byweight of active compound. The percentage of the compound(s) of formula(I) in pharmaceutical compositions and preparations may, of course, bevaried and, for example, may conveniently range from about 2% to about90%, about 5% to about 80%, about 10% to about 75%, about 15% to about65%; about 20% to about 60%, about 25% to about 50%, about 30% to about45%, or about 35% to about 45%, of the weight of the dosage unit. Theamount of compound in therapeutically useful compositions is such that asuitable dosage will be obtained.

Supplementary active compounds may also be incorporated into thecompositions according to the present invention. It is especiallyadvantageous to formulate parenteral compositions in dosage unit formfor ease of administration and uniformity of dosage.

In one embodiment, the carrier may be an orally administrable carrier.

Another form of a pharmaceutical composition is a dosage form formulatedas enterically coated granules, tablets or capsules suitable for oraladministration.

Also included in the scope of this invention are delayed releaseformulations.

Compounds of the invention may also be administered in the form of a“prodrug”. A prodrug is an inactive form of a compound which istransformed in vivo to the active form. Suitable prodrugs includeesters, phosphonate esters etc, of the active form of the compound.

In one embodiment, the compound may be administered by injection. In thecase of injectable solutions, the carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol, and thelike), suitable mixtures thereof, and vegetable oils. The properfluidity can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prevention of the action ofmicroorganisms can be achieved by including various anti-bacterialand/or anti-fungal agents. Suitable agents are well known to thoseskilled in the art and include, for example, parabens, chlorobutanol,phenol, benzyl alcohol, ascorbic acid, thimerosal, and the like. In manycases, it may be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating thecompound/composition in the required amount in an appropriate solventwith one or a combination of ingredients enumerated above, as required,followed by filtered sterilisation. Generally, dispersions are preparedby incorporating the compound/composition into a sterile vehicle whichcontains a basic dispersion medium and the required other ingredientsfrom those enumerated above.

Tablets, troches, pills, capsules and the like can also contain thefollowing: a binder such as gum gragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin or a flavouring agent such as peppermint,oil of wintergreen, or cherry flavouring. When the dosage unit form is acapsule, it can contain, in addition to materials of the above type, aliquid carrier. Various other materials can be present as coatings or tootherwise modify the physical form of the dosage unit. For instance,tablets, pills, or capsules can be coated with shellac, sugar or both. Asyrup or elixir can contain the analogue, sucrose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavouring such ascherry or orange flavour. Of course, any material used in preparing anydosage unit form should be pharmaceutically pure and substantiallynon-toxic in the amounts employed. In addition, the analogue can beincorporated into sustained-release preparations and formulations.

Preferably, the pharmaceutical composition may further include asuitable buffer to minimise acid hydrolysis. Suitable buffer agentagents are well known to those skilled in the art and include, but arenot limited to, phosphates, citrates, carbonates and mixtures thereof.

Single or multiple administrations of the pharmaceutical compositionsaccording to the invention may be carried out. One skilled in the artwould be able, by routine experimentation, to determine effective,non-toxic dosage levels of the compound and/or composition of theinvention and an administration pattern which would be suitable fortreating the diseases and/or infections to which the compounds andcompositions are applicable.

Further, it will be apparent to one of ordinary skill in the art thatthe optimal course of treatment, such as the number of doses of thecompound or composition of the invention given per day for a definednumber of days, can be ascertained using convention course of treatmentdetermination tests.

Generally, an effective dosage per 24 hours may be in the range of about0.0001 mg to about 1000 mg per kg body weight; suitably, about 0.001 mgto about 750 mg per kg body weight; about 0.01 mg to about 500 mg per kgbody weight; about 0.1 mg to about 500 mg per kg body weight; about 0.1mg to about 250 mg per kg body weight; or about 1.0 mg to about 250 mgper kg body weight. More suitably, an effective dosage per 24 hours maybe in the range of about 1.0 mg to about 200 mg per kg body weight;about 1.0 mg to about 100 mg per kg body weight; about 1.0 mg to about50 mg per kg body weight; about 1.0 mg to about 25 mg per kg bodyweight; about 5.0 mg to about 50 mg per kg body weight; about 5.0 mg toabout 20 mg per kg body weight; or about 5.0 mg to about 15 mg per kgbody weight.

Alternatively, an effective dosage may be up to about 500 mg/m². Forexample, generally, an effective dosage is expected to be in the rangeof about 25 to about 500 mg/m², about 25 to about 350 mg/m², about 25 toabout 300 mg/m², about 25 to about 250 mg/m², about 50 to about 250mg/m², and about 75 to about 150 mg/m².

In one embodiment, the compounds as described herein may have a minimuminhibitory concentration selected from the group consisting of about0.0001 to about 1000 μg/ml; about 0.001 to about 500 μg/ml; about 0.001to about 100 μg/ml; about 0.001 to about 50 μg/ml; about 0.01 to about10 μg/ml about 0.04 to about 5 μg/ml; and about 0.04 to about 1 μg/ml.

In one embodiment, the compounds and compositions as described hereinmay also be used to protect medical devices from microbialcontamination. Such antimicrobial protect may be achieved byimmobilizing, for example covalently, the compound or composition to asurface of a medical device, for example a catheter or a medical deviceimplant. Alternatively, the compound or composition could be impregnatedin a non-metal medical device. Impregnation may advantageously providecontinued protection for the device as the surface wears down over timeor through use.

In one embodiment, the compounds and compositions as described hereinmay be applied to a surface as a disinfectant. They may be applied as asolution or in an aerosol.

In another embodiment, a wet wipe in the form of an absorbent sheetcomprising a formulation of the compound or composition as describedherein may be provided. The wet wipe may be used to disinfect surfaces,including hospital, industrial or domestic surfaces such a work tops ora patient's skin prior to, or after, an invasive or other surgicalprocedure.

In another embodiment there is provided a kit comprising a compound orcomposition as described herein and directions for use.

In another embodiment, there is provided a kit comprising thepharmaceutical dosage form as described herein and directions for use.

In another embodiment there is provided the use of a compound orcomposition as described herein, in the preparation or manufacture of amedicament for the treatment of a microbial infection.

In another embodiment, there is provided a method for treating amicrobial infection comprising the step of administering an effectiveamount of a compound or composition as described herein to a patient inneed of such treatment. In one embodiment, the microbial infection maybe caused a bacterial infection caused by a Gram positive or Gramnegative bacteria. In another embodiment, the microbial infection may becaused by Mycobacteria or a fungus.

In one embodiment the Gram negative bacteria may be Pseudomonas spp.

In one embodiment the Gram positive bacteria may be selected from thegroup consisting of Streptococcus spp., Staphylococcus spp., Bacillusspp., Carynebacterium spp., Clostridium spp., Listeria spp., andEnterococcus spp.

In one embodiment, the Staphylococcus spp. is Staphylococcus aureus. Inanother embodiment, the Staphylococcus spp. is Methicillin resistantStaphylococcus aureus(MRSA).

It is an advantage of the compounds as described herein that they areable to eliminate 99.9% MRSA in a sample in 10-20 minutes. It is afurther advantage of the compounds as described herein that they can beused both in vitro and in vivo with minimal cytotoxicity.

In one embodiment, the Streptococcus spp. is Streptococcus epidermis orStreptococcus faecium.

In one embodiment, the Bacillus spp. is Bacillus cereus.

In one embodiment, the Carynebacterium spp. is Carynebacteriumdiptheriae.

In one embodiment, the Clostridium spp. is selected from the groupconsisting of Clostridium botulinum, Clostridium difficile, Clostridiumperfringens, Clostridium tetani and Clostridium sordellii.

In one embodiment, the Bacillus spp. is Bacillus cereus.

In one embodiment, the Listeria spp. is Listeria monocytogenes.

In one embodiment, the Bacillus spp. is Bacillus cereus.

In one embodiment, the Enterococcus spp. is Enterococcus faecalis.

In another embodiment, the microbial infection is a fungal infection.The fungal infection is caused by Cryptococcus gattii, Cryptococcusneoformans, Tinea pedis, Tinea cruris, Tinea corpora, Tinea faciei,Tinea capitis, Tinea manuum, Tinea unguium, Tinia versicolor, Candidaspp., Sporothrix schenckii and Aspergillus spp.

In one embodiment, the microbial disease is caused by includingMycobacterium tuberculosis, Mycobacterium bovis and Mycobacteriumleprae.

In one embodiment, the compound or composition as described herein is tobe administered with one or more further active agents. Combinations ofactive agents, including compounds and compositions as described herein,may be synergistic.

The administration of the medicament as described herein with the one ormore further active agents may be done simultaneously, sequentially orseparately.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings illustrate a disclosed embodiment and servesto explain the principles of the disclosed embodiment. It is to beunderstood, however, that the drawings are designed for purposes ofillustration only, and not as a definition of the limits of theinvention.

FIG. 1 shows a kill curve for MRSA strain DM21455 exposed to compoundAM-016 as described herein.

FIG. 2 shows an absorbance curve of varying concentrations of AM-016 ina saline solution.

FIG. 3 shows an absorbance curve of varying concentrations of AM-016 inwater.

FIG. 4a-4b shows the results of an in vivo cytotoxicity assay on arabbit eye.

FIG. 5 is shows the results of a comparative test for cytotoxicitybetween AM-016 and vancomycin in a rabbit corneal wound healing model.

FIG. 6 graphically illustrates the percentage wound closing in a rabbitcorneal wound healing model over a 3 day period using vancomycin, AM-016or saline solution.

FIG. 7 graphically illustrates a drug resistance curve for vancomycinand AM-016.

FIG. 8. is a plot MICs (μg/mL) of AM016 against E. faecalis ATCC29212,S. aureus DM21455(MRSA), vancomycin intermediate-resistance S.aureus(VISA) and S. aureus ATCC 700699.

FIG. 9 shows the results of a depolarization study of AM-016 withClinical Staphylococcus aureus DM4001(source: Eye).

FIG. 10 shows the results of a depolarization study of AM-005 withClinical Staphylococcus aureus DM4001(source: Eye).

FIG. 11 shows the effect of membrane permeabilization induced bycompounds described herein using SYTOX green assay.

FIG. 12 shows the results of observable SYTOX green fluorescenceemission induced by compounds described herein against Gram-negativebacteria (E. coli ATCC8739).

FIG. 13 shows the effect of membrane permeabilization of compoundsdescribed herein against Gram-positive and Gram-negative bacteria.

FIG. 14 shows fluorescence microscopy images demonstrating that activecompounds as described herein induce a significant amount of SYTOX greenstained S. aureus (fluoresces in green).

FIG. 15 shows the results of an extracellular ATP leakage assay.

FIG. 16 shows the antimicrobial activity of AM-016, vancomycin anddaptomycin against strain MRSA-21455.

FIG. 17 shows show the antimicrobial activity of AM-016, vancomycin anddaptomycin against strain MRSA-09080R.

FIG. 18 shows show the antimicrobial activity of AM-016, vancomycin anddaptomycin against strain MRSA-42412

FIG. 19 shows show the antimicrobial activity of AM-016, vancomycin anddaptomycin against strain MRSA-21595.

FIG. 20 shows show the antimicrobial activity of AM-016, vancomycin anddaptomycin against strain MRSA-700699.

EXAMPLES

Non-limiting examples of the invention, including the best mode, and acomparative example will be further described in greater detail byreference to specific Examples, which should not be construed as in anyway limiting the scope of the invention.

EXAMPLES Example 1—Synthesis of Alpha Mangostin Derivatives

The hydroxyl groups of alpha-mangostin at C3 and C6 position weremodified to mimic an antimicrobial peptide structure, which consists ofa hydrophobic core and cationic side groups. The general modificationstrategy is described below.

The above structure illustrates the general structure of the synthesizedcompounds described herein. Functional groups were introduced to the3,6-position of alpha mangostin to mimic the antimicrobial peptides. “n”refers to the length of link space, from 1 to 20. The R— moieties areselected from different functional group, such as halogen, aliphaticamines, aromatic amines, amino acid, guanidine and the like. Thealpha-mangostin based synthetic antibiotics were classified into threetypes by the properties of the R— functional groups, including cationicmodification, neutral modification and anionic modification.

1.1 Cationic Modification of Alpha-Mangostin Synthesis of CationicAlpha-Mangostin Derivatives by Dibromo-Substituted Approach.

We first synthesized different length spacers of w-bromoalkylsubstituted alpha mangostin, the length of the spacer was from 2-20. Theintermediates were conjugated with three types of amines to obtaincationic modification of the alpha-magostin derivatives. These threetypes of amines including linear aliphatic amines such as ethanamine,propan-1-amine, dimethylamine, diethyl amine, dipropylamine,diisopropylamine, triethylamine, trimethylamine, tripropylamine,n-propylpentan-1-amine, butan-1-amine; cyclic aliphatic amines such asthiazolidine, isoxazolidine, oxazolidine, pyrrolidine, morpholine,piperazine, thiomorpholine, 1-methylimidazolidine; and aromatic aminessuch as 1,2,4-triazole, 1H-imidazole, pyrazole, pyridine, pyridazine,pyrimidine, 1H-1,2,3-triazole and the like (see Scheme 1-1)

Scheme 1-1

The general synthesis route of cationic alpha-mangostin derivatives bydibromo-substituted approach.

Specific examples of this type of analogue are illustrated as below:

Synthesis of AM005

alpha-Mangostin (1.0 g, 2.44 mmol) was dissolved in 15 mL of acetone,then potassium carbonate (1.6 g, 12.20 mmol) and 1,4-dibromobutane (4.34mL, 36.6 mmol) were added. The mixture was refluxed for 24 h. After thereaction was completed (TLC), the solvent was removed under reducedpressure. The oil residue was diluted with EtOAc and washed twice withsaturated brine and once with water. The organic phase was dried overanhydrous Na₂SO₄ then purified via silica gel column chromatography(petroleum ether/EtOAc, 20/1, v/v), affording 1.27 g of product AM005 asa light yellow solid in 76.5% yield.

Synthesis of AM012

To a solution of AM005(100 mg, 0.147 mmol) in acetone (4 mL),1H-pyrazole (100 mg, 1.47 mmol) and potassium carbonate (101 mg, 7.35mmol) were added. The mixture was refluxed for 48 h. After the end ofthe reaction, the solvent was removed under reduced pressure. Theresidue was diluted with 50 mL of ethyl acetate and washed three timeswith saturated brine, dried over anhydrous Na₂SO₄. After removal ofsolvent, the residual mixture was purified via silica gel columnchromatography (EtOAc/MeOH/Et3N, 100/2/1, v/v), affording 73.9 mg ofproduct AM012 as a light yellow solid in 76.8% yield.

Synthesis of AM016

To a solution of AM005(100 mg, 0.147 mmol) in DMSO (4 mL), diethylamine(4 mL) was added. The mixture was stirred at room temperature for 3 h.After the end of the reaction, the mixture was diluted with 50 mL ethylacetate, then washed with aqueous NaHCO₃ and saturated brine (each threetimes). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The residual crude oil was purified viasilica gel column chromatography (EtOAc/MeOH/Et3N, 100/2/1, v/v),affording 80.8 mg of pure product AM016 as a yellow oil in 82.7% yield.

1.1.2 Synthesis of Cationic Alpha-Mangostin Derivatives by aDicarboxyl-Substituted Approach.

Cationic modified alpha-mangostin derivatives were synthesized using adicarboxyl substituted alpha-mangostin derivative. In order to obtaincationic modification alpha-mangostin derivatives, the intermediate wasconjugated with different types of amines or peptides, such as arginine,histidine, lysine, spermidine, N,N-dimethyldipropylenetriamine,diethylenetriamine, ethanamine, N,N-diethyldiethylenetriamine,triethylenetetramine, pentaethylenehexamine, ethylenediamine,propan-1-amine, dimethylamine, diethylamine,1,3-di-boc-2-(2-hydroxyethyl)guanidine et al. Some of this AM seriesanalogues, especially AM-052, showed excellent antimicrobial activityagainst Gram-positive and Gram-negative bacteria, low cytotoxicity witha lower hemolytic activity with HC₅₀ of 238 μg/mL.

Scheme 1-2

General synthesis route of key intermediate compounds ofdicarboxyl-alkyl-substituted mangostin and some target molecules ofcationic modification of alpha-mangostin by mimicking of AMPs.(Arg=Arginine, Lys=Lysine, His=Histidine).

Specific examples of this type of analogue are illustrated as below:

Synthesis of AM050

A mixture of alpha-mangostin (0.5 g, 1.22 mmol), methyl bromoacetate(1.12 g, 7.3 mmol) and KOH (341.6 mg, 6.1 mmol) in ethanol (30 mL) wasrefluxed for 72 h. After cooling down, the mixture was diluted withethyl acetate and washed with 3 times NaCl solution (3×50 ml). Organicphase was dried over anhydrous sodium sulfate. The solvent wasevaporated to give crude product as oil. And then continue the next stepreaction without further purification.

Synthesis of AM051

To a solution of AM50 in 20 ml THF, was added a solution of LiOH(87.84mg, 3.66 mmol) in 10 ml water. After stirring at room temperature for 2h, DCM was added and the layers were separated. The mixture was washedwith 3 times DCM (3×20 ml). And then the aqueous layer was acidifiedwith diluted hydrochloric acid. The mixture was diluted with butanol andwashed with 3 times NaCl solution (3×50 ml). Organic phase was driedover anhydrous sodium sulfate. The solvent was evaporated to generatecrude residue, which was purified by column chromatography (silica gel,PE/EtOAc/CH₃COOH, 3:1:0.04) to give 345.6 mg yellow solid. The two stepyield is 53.8%.

Synthesis of AM052

HOBt (64.1 mg, 0.475 mmol) was added to AM51(100 mg, 0.19 mmol) inanhydrous DMF (5 mL). At −10° C., DIC (59.9 mg, 0.475 mmol),H-Arg-OMe·2HCl (124 mg, 0.475 mmol) were added, and stir at −10° C. for1 h. After stirring at room temperature overnight, the mixture wasdiluted with ethyl acetate and washed with 3 times NaCl solution (3×50ml). Organic phase was dried over anhydrous sodium sulfate. The solventwas evaporated to generate crude residue, which was purified bychromatography to give yellow solid.

1.1.3 Synthesis of Cationic Alpha-Mangostin Derivatives by DiepoxyEthyl-Substituted Approach.

Cationic modified alpha-mangostin derivatives were also synthesizedusing diepoxy ethyl-substituted alpha mangostin derivatives. In order toobtain cationic modification alpha-mangostin derivatives, theintermediate was conjugated with different types of amines, such asethanamine, propan-1-amine, dimethylamine, diethyl amine, dipropylamine,diisopropylamine, triethylamine, trimethylamine, tripropylamine,n-propylpentan-1-amine, butan-1-amine, thiazolidine, isoxazolidine,oxazolidine, pyrrolidine, morpholine, piperazine, thiomorpholine,1-methylimidazolidine, 1,2,4-triazole, 1H-imidazole, pyrazole, pyridine,pyridazine, pyrimidine, 1H-1,2,3-triazole and the like. (see Scheme1-3).

Scheme 1-3

General synthesis route of key intermediate compounds of diepoxysubstituted mangostin and target molecules of cationic modification ofalpha-mangostin.

Specific examples of this type of analogue are illustrated as below:

Synthesis of AM058

A mixture of alpha-mangostin (0.5 g, 1.22 mmol),1-bromo-2,3-epoxypropane (2.507 g, 18.3 mmol) and KOH (341.6 mg, 6.1mmol) in ethanol (30 mL) was refluxed for 24 h. After cooling down, themixture was diluted with ethyl acetate and washed with 3 times NaClsolution (3×50 ml). Organic phase was dried over anhydrous sodiumsulfate. The solvent was evaporated to generate crude residue, which waspurified by column chromatography (silica gel, PE/EtoAc/, 3:1) to giveyellow solid (yield: 133.9 mg, 21%)

Synthesis of AM059

To a solution of AM058(100 mg, 0.191 mmol) in methanol (4 mL),diethylamine (2 mL) was added. The mixture was refluxed for 6 h. Afterthe end of the reaction, the mixture was evaporated to remove the excessamine and solvent, and then diluted with 40 mL ethyl acetate, thenwashed with aqueous NaHCO₃ and saturated brine (each three times). Theorganic phase was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The residual crude oil was purified purified by columnchromatography (silica gel, EtOAc/MeOH/Et₃N, 100/2/0.5, v/v) to giveyellow solid. (yield: 93.3 mg, 73.1%).

1.2 Synthesis of Anionic Modification of Alpha-Mangostin.

In addition to the cationic modification of alpha-mangostin, anionicmodifications of alpha-mangostin were synthesized (see Scheme 1-4).

Scheme 1-4

General synthesis of anionic alpha-mangostin analogues.

Specific examples of this type of analogue are illustrated as below:

Synthesis of AM071 and AM072

Alpha-mangostin (201.6 mg, 0.491 mmol) was reacted with chloroaceticacid (826.8 mg, 8.75 mmol) and NaOH (0.576 mg) in DMSO (5 ml) withstirring at 75° C. for 72 h. The reaction mixture was cooled down andhydrochloric acid was added until no additional precipitate was formed.Solvent was removed, then the residual oil was washed 3 times withsaturated NaCl solution. The organic extracts were combined and driedovernight with anhydrous Na₂SO₄. Solvent was removed under reducedpressure. The resulting residue was purified by column chromatography(PE/EtoAc/AA,70/40/1,V/V/V). Yield: AM071, 45.2%; AM072, 16.9%

1.3. Neutral Hydrophilic Modification of Alpha-Mangostin.

Neutral modified alpha-mangostin derivatives were synthesised. Incontrast to cationic and anionic modified alpha mangostin, neutralfunctional group without charge carrier such as halogens, alkyl groups,sulfonamide or polyethylene glycols (PEG) were used to modify thealpha-mangostin structure (see Scheme 1-5)

Scheme 1-5

General synthesis of AM series of PEG-mangostin conjugate

The specific examples of this type of analogue are illustrated below:

Synthesis of AM-076

A mixture of alpha-mangostin (100 mg, 0.244 mmol), PEG-OTs (0.4542 g,0.502 mmol) and K₂CO₃(0.0488 g, 0.353 mmol) in DMF (5 ml) was stirred at100° C. After the end of the reaction, the mixture was diluted withethyl acetate and washed 3 times with NaCl solution. The resultingresidue was purified by silica gel column chromatography (EtoAc/MeOH,5/3, V/V) to give compound AM-076 as a brownish-yellow liquid in yieldof 57.1%.

Example 2 Biological Activity 2.1 Minimum Inhibition Concentrations(MIC) and Selectivity.

The following tables show the antimicrobial activity of some of thecompounds described herein.

TABLE 2-1 Antibacterial Activity (MIC), in vitro toxicity (HC₅₀) andSelectivity of α-mangostin derivatives. pKa of conjugated MIC₉₉ [μgmL⁻¹] HC₅₀ [μg Selectivity [HC₅₀/MIC₉₉] Compound n R amine, R—H MRSA^(b)S. aureus ^(c) mL⁻¹]^(a) MRSA S. aureus AM-011 3

10.98 0.39 0.78 16.27 41.72 20.86 AM-016 4

10.98 0.39 0.39 19.6 50.26 50.26 AM-008 5

10.98 0.78 1.56 14 17.95 8.97 AM-010 6

10.98 1.56 1.56 26.5 16.99 16.99 AM-015 4

11.27 1.56 1.56 25 16.03 16.03 AM-017 4

11.22 1.56 0.78 19.25 12.34 24.68 AM-009 4

8.36 >200 >200 >200 —^(d) — AM-012 4

2.52 >200 >200 >200 — — AM-002 4

2.20 >200 >200 >200 — — AM-005 4 Br NA^(e) >200 >200 >200 — — AM-000 0 HNA 1.56 1.56 9 5.77 5.77

Example 2—Antimicrobial Activity of Alpha-Mangostin Derivative AM016

The anti-microbial activity ofAM016(3,6-bis-[4-(diethylamino)butoxy)]-1-hydroxy-7-methoxy-2,8-bis(3-methylbut-2-enyl)-9H-xanthen-9-one;or 3,6-O-bis[4-(diethylamino)butyl]-α-mangostin) was tested.

As can be seen in Table 1A, compound AM0016 demonstrates very goodantimicrobial activity against Gram positive bacteria, specifically aseries of MRSA strains. Table 1a and 1b show the minimum inhibitionconcentration (MIC) (μg/ml)/((μM) of compound AM-016 needed forantimicrobial activity.

AM-016 also demonstrates a broad antimicrobial activity against Gramnegative bacteria. AM016 is also effective against

Gram negative bacteria (Table 1b).

AM-016 eliminates 99.9% of MRSA in a sample within 20 minutes ofapplication (FIG. 1)

TABLE 1a AM-016 AM-016 MRSA strain (μg/ml) (μM) MRSA DM21455 0.39 0.59Source: Eye Clinical 1.56 2.35 Staphylococcus aureus DM4001 Source: EyeMRSA DM09808R 1.56 2.35 Source: Eye Clinical 0.78 1.17 Staphylococcusaureus DM4400R Source: Cornea Clinical 0.78 1.17 Staphylococcus aureusDM4583R Source: Eye MRSA DB57964/04 0.78 1.17 Clinical 1.56 2.35Staphylococcus aureus DM4299 MRSA DM21595 0.78 1.17 Source: Wound MRSADR42412 1.56 2.35 Source: Sputum MRSA DR68004 1.56 2.35 Source: BloodMRSA QC Strain 3.125 4.70 ATCC BAA1026 Staphylococcus 0.39 0.59 aureusATCC29213 Staphylococcus 1.56 2.35 aureus ATCC 6538 Straphylococcus 0.781.17 aureus ATCC 6538P Straphylococcus 1.56 2.35 aureus ATCC 29737Straphylococcus 3.125 4.70 aureus ATCC 25923

TABLE 1b AM-016 AM-016 Bacteria strain (μg/ml) (μM) Streptococcus 0.1950.295 faecium ATCC 10541 Streptococcus 0.78 1.17 epidermidis ATCC 12228Bacillus cereus 3.125 4.70 ATCC11778 Pseudomonas 50 75.20 aeruginosaATCC27853 Klebsiella 40 60.16 pneumoniae ATCC10031 Enterococcus 0.781.17 faecalis ATCC 29212Table 1a and 1b: Minimum inhibition concentration (MIC) (μg/ml)/(μM) ofcompound AM-016 for eliminating Gram positive and Gram negativebacteria.

Example 2—Antimicrobial Activity of AM-052 Against Against MRSA andGram-Negative Bacteria

AM-052 shows excellent antimicrobial activity against MRSA andGram-negative bacteria, with low hemolytic activity with HC50 of 238(μg/mL) (See Table 3).

TABLE 2 Summary of MIC99 (μg/mL), HC50 (μg/mL) and Selectivity Index ofAM-052 Strain of Selectivity bacteria MIC99 HC50 Index Methicillin-3.125 238 76 resistant Staphylococcus aureus DM09808R Methicillin- 1.56238 153 resistant Staphylococcus aureus DM21455 Source: EyeStaphylococcus 6.25 238 38 aureus ATCC 29213 Bacillus cereus 3.125 23876 ATCC 11778 Pseudomonas 12.5 238 19 aeruginosa ATCC27853 Klebsiella6.25 238 38 pneumoniae ATCC10031

Example 3—Basic Physiochemical Properties of AM016 and AM052 3.1Solubility

Table 3-1 shows the solubility of compounds AM016 and AM052 in differentmedia.

TABLE 3-1 Solubility (ug/ml) Solvents AM016 AM052 Water 72.1 ± 3.6 >2mg/ml Saline 133.3 ± 11.5 >1 mg/ml DMSO >7 mg/ml >2 mg/ml PBS >3 mg/mlnot soluble

Table 3-1: Solubility of AM016 and AM052 in Different Media

The determination of solubility was made as follows: AM016 with knownweight was added with 1 mL saline, pure water or phosphate buffer saline(PBS) 20 mM at pH7. The solvent was added stepwise until the compoundwas dissolved completely. Then, the stock solution was diluted to seriesof diluents and the absorbance of each diluent was determined.

In PBS buffer AM-016 has excellent solubility. The solubility in PBS is3 mg/ml.

In saline solution FIG. 2 shows that the solubility of AM016 is 130μg/mL.

In pure water solubility is 70 μg/ml, see FIG. 3.

3.2 pH Value of AM016 and AM052 in Different Media

TABLE 3-2 pH value of AM016 in different media ConcentrationConcentration of compound pH of of compound pH of Solvents (μg/ml)AM0016 (μg/ml) AM052 Water 50 6.44 ± 0.27 50 6.52 ± 0.29 70 6.72 ± 0.23100 7.66 ± 0.33 Saline 50 6.84 ± 0.21 50 5.33 ± 0.05 100 6.78 ± 0.05 1005.33 ± 0.01 PBS 50 6.96 ± 0.01 50 — 100 6.97 ± 0.01 100 —The pH values were obtained using an electronic pH meter.

Example 4—Minimum Inhibition Concentration (MIC) (μg/Ml)/(μM) ofCompounds AM002, AM005, AM008, AM009, AM010

AM002, AM005, AM008, AM009, AM010 were tested against Gram positivebacteria including several strains of Staphylococcus aureus. The resultsare shown in Table 2. It can be seen that compounds AM008, AM009 andAM010 display very good antimicrobial activity against certain strainsof Staphylococcus aureus. AM-005, which is a neutral hydrophobicmodification of alpha-mangostin by incorporation of dibromo alkylsubstitutions, did not show activity against Gram-positive bacteria at50 ug/ml (see Table 4).

TABLE 4 Minimum inhibition concentration (MIC) (μg/ml)/(μM)of compoundsAM002, AM005, AM008, AM009, AM010 MRSA MRSA MRSA Clinical DM09808RDM21455 DM21595 Staphylococcus Bacilus Staphylococcus Source: Source:Source: aureus Cereus aureus S/N Eye Eye Eye DM4001 ATCC11778 ATCC29213AM- >50 ND ND ND >50 >50 002 AM- >50 >50 ND ND ND >50 005 AM- 0.78 1.56008 AM- >25 >25 009 AM- 1.56 1.56 010 Staphylococcus KlebsiellaPseudomonas Escherichia aureus pneumoniae aeruginosa coli S/N ATCC6538ATCC10031 ATCC27853 ATCC8739 AM- ND >100 30 >100 002 AM- ND ND >50 ND005

Example 5—Biological Activity of Compounds AM071 and AM072

Table 5 shows the biological activity of compounds AM071 and AM072against certain strains of Gram positive bacteria.

TABLE 5 MIC data of AM-071 and AM-072 for Gram positive bacteria AM-071AM-071 AM-072 AM-072 Bacteria (μg/ml) (mM) (μg/ml) (mM) MRSA DM21455 2553.36 6.25 13.34 Source: Eye Bacillus cereus 6.25 13.34 6.25 13.34ATCC11778 Clinical 25 53.36 6.25 13.34 Staphylococcus aureus DM4001Source: Eye Staphylococcus aureus 12.5 26.68 6.25 13.34 ATCC29213 As canbe seen from Table 5 above, compounds AM071 and AM072 do not demonstratevery good antimicrobial activity against Staphylococcus aureus orBacillus cereus

Example 6—In Vivo Cytotoxicity Test of AM-016

AM-016 does not show cytotoxicity in the rabbit eye after 3 days ofapplication of drug (FIGS. 5a and b ).

Initial testing was carried out on a rabbit eye, using five applicationsper day at a concentration of 400 μg/mL (513-1026×MIC). No observabletoxic effect was observed on the mouse cornea after AM016 was appliedtopically. FIG. 5a shows the rabbit eye before application of AM016 andFIG. 5b shows the rabbit eye after topical application of AM016.

Example 7—Effect of AM016 on Wound Healing of Rabbit Cornea

FIG. 5 shows the results of a comparative test for cytotoxicity betweenAM-016 and vancomycin in a rabbit corneal wound healing model. Theparticular model used was a 5 mm diameter corneal epithelial abrasionmodel. Wound healing was monitored by a slit lamp using flouresceindisclosure dye so that the size of the wound could be measured. Thecompounds were applied topically three times per day.

As can be seen AM-016 does not exhibit any cytotoxicity to the rabbiteye after 3 days of application of drug (see FIG. 5) compared with anormal control.

FIG. 6 graphically illustrates the percentage wound closing over thesame 3 days using vancomycin, AM-016 or saline solution. As can be seen,the application of AM-016 does not delay wound healing indicating thatAM-016 does not display any cytotoxic effects.

Example 8—Drug Resistance Test of AM-016 with a MRSA Strain from an Eye

FIG. 7 shows that MRSA DM21455 has difficulty in developing drugresistance towards AM-016 during 20 serial passages of bacteria grown inmedia with a constant concentration of AM-016. In contrast, MRSA DM21455develops drug resistance more quickly against vancomycin when comparedto AM-016.

FIG. 8 shows the results of a multipassage resistance selection study toinvestigate the propensity of S. aureus and Enterococcus faecalis todevelop endogeneous mutational resistance against AM016 during prolongedpassages at the sub-inhibitory concentrations.

Resistance is defined as >4-fold increase in the original MIC developedin the multipassage study. FIG. 8 shows that there was no evidence ofresistance or cross-resistance against AM016 in any of the 4 strainstested.

Example 9—Action Mechanism Study of AM-016

Membrane potential-sensitive dye 3,3′-dipropylthiadicarbocyanine iodide(DiSC3) was used to determine the cytoplasmic membrane depolarizationactivity of AM-016.

An overnight culture of clinical Staphylococcus aureus DM4001(source:Eye) was allowed to grow in Muller-Hinton broth (MHB) to OD620=0.3-0.4.Then, the bacteria was collected by centrifugation at 2800 r.p.m at 37°C. for 30 minutes and washed with 5 mM HEPES buffer at pH7. Then, thebacteria were re-suspended in the same buffer with with 0.2 mM EDTA toobtain an OD620 value of 0.9-0.1. The cell suspension was then incubatedwith 0.1M KCl and 0.4 μM DiSC3 at 37° C. for 30 minutes. Dye uptake wasmonitored by fluorospectrometry (Photon Technology International (PTI)Photomultiplier Detection Systems, model 814) in a stirred cuvette untilthe fluorescence signal was stable. The desired concentration of AM-016was added and the fluorescence was monitored at an excitation wavelengthof 622 nm and at an emission wavelength of 670 nm. A blank with dye inthe absence of bacteria with same concentration of AM-016 was used as acontrol.

FIG. 9 shows that when 12.5 ug/mL of AM-016 was added to the S. aureusculture, fluorescence increases. This signifies that AM-016 causesmembrane depolarization and therefore DISC₃ was released into medium andresults in an increase in fluorescence. Thus, AM-016 is a potentialmembrane-target antimicrobial agent which is able to disrupt ordissipate the membrane potential of Gram positive bacteria. In contrast,interestingly, its precursor dibromo-substituted AM-005 (withouttertiary amine as terminal groups) does not depolarize the membrane(FIG. 10).

In addition, time killing (see FIG. 1) and drug resistance (FIGS. 7 and8) also support the suggested depolarization mechanism of AM-016.

FIG. 1 shows that more than 99.9% MRSA was killed within 20 minutes. Formembrane targeted antimicrobial agents, the elimination time is veryfast as the uptake of antimicrobial agent by the bacteria is not needed.The bacteria will be killed upon contact with antimicrobial agent.

FIG. 7 shows that MRSA has difficulty in developing drug resistancetowards AM-016 during 20 serial passages. To develop drug resistanceagainst a membrane target antimicrobial agent, bacteria have to changethe composition of the cell wall or membrane to prevent interaction ofthe membrane with the antimicrobial agent. However, for substantialchanges in the membrane composition to occur, the bacteria must undergomultiple rounds of mutation which may ultimately be incompatible withbacterial survival [1]. Vancomycin is an antimicrobial used to treatMRSA infection. The antimicrobial action mechanism of vancomycininvolves inhibition of peptidoglycan polymerization. Drug resistance inStaphylococcus aureas is more pronounced for vancomycin when comparedwith AM-016. Taken together these results strongly suggest that AM-016targets the membrane of bacteria and other microbes.

The depolarization study strongly suggests that AM-016 depolarizes aclinical S. aureus DM4001 bacteria membrane. In contrast the precursordibromo-alkyl substituted AM-005 (without tertiary amine as terminalgroups) does not depolarize the membrane. This result supports the MICscreening, the time killing and drug resistance results presented above.

SYTOX Green Assay

SYTOX green is a membrane impermeable dye. Interaction of SYTOX greenwith a nucleic acid enhances the fluorescence emission of SYTOX greensignificantly. S. aureus DM4001 was harvested at early exponential phaseand suspended in 40 mM PBS until OD₆₂₀ of 0.09 was obtained. Then, thebacteria suspension was incubated with 3 μM of SYTOX Green in dark. Themixture was monitored in a stirring cuvette at an excitation wavelengthof 504 nm and at an emission wavelength of 523 nm until the fluorescencewas stable. Then, 10 μM of AM compounds were added and the changed offluorescence emissions were monitored. FIG. 4-2A shows thatantimicrobial active compounds (AM-008, AM-010, AM-010, AM-011, AM-015,AM-016, AM-017) could induce membrane permeabilization and enhance theSYTOX green fluorescence emission. In contrast, inactive compoundsincluding AM-002, AM-005, AM-009, AM-012, AM-044 and AM-045 were notable to trigger the membrane permeabilization (see FIG. 11). AM-043 hadweaker membrane permeabilization effect.

AM-008, AM-010, AM-011, AM-016, AM-015 and AM017 were found to be activeagainst Gram-positive bacteria but inactive against Gram-negativebacteria. To further confirm that membrane permeabilization is importantto kill the bacteria, the SYTOX green assay was tested using E. coliATCC8739. FIG. 12 shows that addition of all AM-series compounds testeddid not induce membrane permeabilization of E. coli as there was noobservable increased of SYTOX green fluorescence emission. FIG. 13 showsthe membrane permeabilization effects of selected compounds (activeagainst Gram-positive bacteria) on Gram-positive and Gram-negativebacteria. The data clearly suggest that membrane targeting and innermembrane permeabilization are crucial for the compounds described hereinto kill the bacteria.

In addition to the fluorescence spectroscopy, we further confirm theinner membrane targeting properties of active AM-series compounds usingfluorescence microscopy (FIG. 14). Large numbers of stained bacteriawere observed in the culture incubated with active AM-series compounds(AM-008, AM-010, AM-011, AM-015, AM-016, AM-017) at 10 μM, clearlyindicating that these AM-series compromised the living bacterialcytoplasmic membrane. In contrast, no significant staining was notobserved in the culture treated with inactive compounds (AM-002, AM-005,AM-009, AM-012, AM-044, AM-045).

Calcein Leakage Study

To further investigate antimicrobial action of the active compounds viainner membrane targeting, a calcein leakage study was performed. Inbrief, liposomes which mimic bacterial membrane (DOPE: DOPG=3:1) and redblood cell (DOPC: DOPS=3:1) were synthesized. The lipids were dissolvedin methanol/chloroform (1:2, by volume). The solvent was then driedgently using a constant stream of nitrogen gas. Then, the lipid film wasplaced under vacuum for at least two hours. The dried lipid film wasthen hydrated with calcein solution (80 mM calcein, 50 mM HEPES, 100 mMNaCl, 0.3 mM EDTA, pH 7.4). The hydrated vesicles were freeze-thaw(frozen in liquid nitrogen and warmed in water bath) for at least 7cycles. Extrusion method using mini-extruder (Avanti Polar Lipid Inc.)was used to produce homogeneous large unilamellar vesicles (LUVs). Theextrusion was done for at least 10 cycles using a polycarbonate membrane(Whatman, pore size 100 nm) to obtain LUVs with diameter of 100 nm. Toseparate the calcein encapsulated vesicles from free calcein, gelfiltration column Sephadex G-50 was used. The concentrations of elutedliposomes were determined using total phosphorus determination assay.Leakage of calcein from the liposome induced by AM-series compoundscould be monitored using fluorescence spectroscopy (Photon TechnologyInternational Model 814) at an excitation wavelength of 490 nm and anemission wavelength of 520 nm. An aliquot of the LUV suspension andlipid to AM-series compounds ratio of 2, 4 and 8 were mixed in a stirredcuvette and the fluorescence emission intensity was monitored. 0.1%Triton X-100 was use to determine the intensity at 100% leakage.Percentage of leakage (% L) was calculated with %L=[(I_(t)−I₀)/(I_(∞)−I₀)]*100], where I₀ and I_(t) are intensity beforeand after addition of α-mangostin respectively and I_(∞) is intensityafter addition of 0.1% triton X-100. Table 4-3A shows the % calceinleakage from the liposome (DOPE:DOPG=3:1) induced by AM-seriescompounds. Inactive xanthones did not induce observable leakage up tocompound to lipid ratio of 1:2. In addition, active AM-series compoundsare also able to induce leakage of calcein from DOPC:DOPS=3:1 liposomes,which corroborate with the HC50 values for the compounds (Table 4-3B).Those compounds with high low HC50 values have stronger leakage %.Compounds with high HC50 values show negligible calcein leakage (<10%).To further investigate the inner membrane targeting action of AM-seriescompounds, E. coli lipid extract was used to construct the liposome.Although all AM-series compounds are inactive against E. coli,surprisingly, AM-010, AM-011, AM-008, AM-015, AM-016, AM017 were able toinduce leakage of calcein from the E. coli lipid extract (Table 4-3C).Therefore, the outer layer of Gram-negative bacteria (LPS) may playimportant role to impede the AM-series compounds to reach innermembrane. Calcein leakage data strongly support the active compounds areinner membrane targeting.

TABLE 6 Percentage leakage of calcein from DOPE:DOPG = 3:1 liposomesinduced by compounds as described herein. % Leakage AM-series compounds:Lipid ratio Liposome (DOPE:DOPG = 3:1) 1:2 1:4 1:8 AM-011 52.35 60.39AM-016 54.43 37.00 21.00 AM-008 61.50 55.00 36.46 AM-010 67.00 54.3446.57 AM-015 AM-017 AM-002, AM-012, AM-009, <10 AM-005

TABLE 7 Percentage leakage of calcein from DOPC:DOPS = 3:1 liposomesinduced by compounds described herein. % Leakage AM-series compounds:Lipid ratio Liposome (DOPE:DOPG = 3:1) 1:2 1:4 1:8 AM-011 75.19 58.1934.10 AM-016 88.43 72.76 37.66 AM-008 90.87 61.34 33.54 AM-010 91.0062.05 37.31 AM-015 AM-017 AM-002, AM-012, AM-009, <10 AM-005

TABLE 8 Percentage leakage of calcein from E. coli lipid extract inducedby compounds described herein. % Leakage AM-series compounds: Lipidratio Liposome (E. coli extract) 1:2 1:4 1:8 AM-011 69.52 14.72 5.05AM-016 57.82 58.43 31.70 AM-008 79.97 50.49 24.06 AM-010 73.85 48.1128.51 AM-015 AM-017 AM-002, AM-012, AM-009, <10 AM-005

Extracellular ATP Leakage Assay

ATP leakage assay is also an important assay to study the inner membranetargeting property of a compound. ATP is released from a membranecompromised cells and the amount of ATP released can be detected. Incontrast, if a compound does not induce membrane disruption, minimum ATPreleased will be detected. In this study, a bioluminescence assay wasused using recombinant firefly luciferase and its substrate D-luciferin.ATP is required for luciferase to interact with luciferin to producelight. First, bacteria suspension (OD=0.4) was incubated with AM-seriescompounds with desired concentration at 37° C. for 10 minutes. Then, thesuspension was centrifugated at 3000 r.p.m. for 5 minutes. Standardreaction solution containing 0.5 mM D-luciferin, 1.25 μg/mL fireflyluciferase, 25 mM Tricine buffer at pH 7.8, 5 mM MgSO₄, 100 μM EDTA and1 mM DTT was prepared and added into 96 well plates. 10 uL ofsupernatant of the culture solution was added and the ATP released wasdetermined using Luminometer (TECAN Infinite M200Pro). 8 μM of nisin wasused to trigger complete ATP leakage. FIG. 4-4 shows the ATP leakageinduced by the AM-series compounds. Compounds active againstGram-positive bacteria could induce strong ATP leakage. In contrast,inactive compounds were not able to induce ATP leakage. The resultfurther shows that active AM-series compounds are inner membranetargeting (see FIG. 15).

The results of the antimicrobial action studies clearly show thatAM-series compounds are inner membrane targeting. The mechanism is wellcorrelated with the antimicrobial properties of active AM-seriescompounds such as AM016. FIG. 1 shows that more than 99.9% MRSA waskilled within 20 minutes. For membrane target antimicrobial, the timekilling is very fast as the uptake of antimicrobial by the bacteria isnot needed. The bacteria will be killed upon it contacts with membranetarget antimicrobial.

In addition, FIGS. 6 and 7 show that MRSA is difficult to develop drugresistance against AM-016 during 20 serial passages. To develop drugresistance against membrane target antimicrobial, bacteria have tochange the compositions of cell wall or membrane to prevent theinteraction with membrane target antimicrobial. However, tremendouslychanged of membrane composition requires multiple mutation and suchalternation might be incompatible with cellular survival.

Example 10—Antimicrobial Activity of AM-016 Compared with Vancomycin andDaptomycin Against Various Strains of Staphylococcus aureus

The antimicrobial activity of AM-016 was compared with vancomycin anddaptomycin against various strains of Staphylococcus aureus using theMueller Hinton broth dilution method.

FIGS. 16 to 20 show the antimicrobial activity of AM-016, vancomycin anddaptomycin against various strains of Staphylococcus aureus. As can beseen AM-016 exhibits antimicrobial activity (as determined by theminimum inhibitory concentration in μg/ml) against strainsMRSA-21455(see FIG. 16), MRSA-09080R (see FIG. 17), MRSA-42412(see FIG.18), MRSA-21595(see FIG. 19) and MRSA-700699(see FIG. 20). AM-016 showssuperior antimicrobial activity against strains MRSA-09080R, MRSA-21595and MRSA-42412 when compared to vancomycin. However, AM-016 showssuperior antimicrobial activity against MRSA-700699 when compared toboth daptomycin and vancomycin, with a minimum inhibitory concentrationof 0.048 μg/ml.

The minimum inhibitory concentrations (MIC) are as follows:

MIC values (μg/ml) Daptomycin Vancomycin AM-016 MRSA-21455 (Eye) 0.780.78 1.56 MRSA-09808R (Eye) 0.195 0.395 3.125 MRSA-42412 (Sputum) 0.1950.78 0.395 MRSA-700699 0.78 6.25 0.095 MRSA-21595 (Wound) 0.395 0.780.395

The minimum inhibitory concentrations for AM-016 and vancomycin againstcertain other strains of Gram positive bacteria are also presented below

Strains AM-016 Vancomycin Enterococcus faecalis 1.56 50 ATCC 51299 VREEnterococcus faecalis 11: 0.098 Above 100 DS6527 (VRE 208/11)Enterococcus faecalis 11: 0.78 1.56 DU9345 VRE Staphylococcus aureus 10:0.78 1.56 DB6506 (MRSA04/10) (VISA) Staphylococcus aureus 0.39 6.25 ATCC700699 (VISA)As can be seen, AM-016 demonstrates superior antimicrobial propertiescompared to vancomycin.

Example 11—Antimicrobial Activity of Alpha-Mangostin DerivativeCompounds Against Mycobacterium tuberculosis

Table 10 shows the antimicrobial activity of some alpha mangostinderivatives described herein against Mycobacterium tuberculosis.

TABLE 10 Antimicrobial activity against Mycobacterium tuberculosis,hemolytic activity and selectivity index of some typical AM-seriescompounds. MIC100 Hemolytic nmol/ml concentration, Selectivity Codenumber Mw (μg/ml) HC50 (μg/ml) index AM000 410.46 NI 6.5 (alpha-mangostin) AM002 656.77 NI AM005 680.46 NI AM008 692.97 4 (2.77) 14 5.05AM009 692.88 8 (5.54) >1000 >180 AM012 654.79 NI AM-013 396.43 125(49.55)  25 0.50 (Gamma- mangostin) AM015 660.88 4 (2.64) 25 9.46 AM016664.91 4 (2.66) 19.6 7.37 AM071 526.53 250 37.5 0.28 AM072 556.64 250 NDEthambutol 204.31  20 Note: NI: no activity at 250 nmol/mL

As can be seen from the results presented in Table 10 AM-009 appears tohave the best selectivity against Mycobacterium tuberculosis.

REFERENCES

-   [1] Ooi, et al, XF-73, a novel antistaphylococcal membrane-active    agent with rapid bactericidal activity, Journal of Antimicrobial    Chemotherapy (2009)64, 735-740.

APPLICATIONS

It will be apparent that various other modifications and adaptations ofthe invention will be apparent to the person skilled in the art afterreading the foregoing disclosure without departing from the spirit andscope of the invention and it is intended that all such modificationsand adaptations come within the scope of the appended claims.

1.-36. (canceled)
 37. A compound of Formula (II) or a pharmaceuticallyacceptable salt thereof:

wherein m is 1; Y is O; B is NR¹¹R²⁴; each of R³ and R¹⁰ isindependently hydrogen or alkyl; R⁴ and R⁵ taken together with thecarbon to which they are bonded form (C═O); R⁶ and R⁷ taken togetherform a bond; R⁸ and R⁹ taken together form a bond; R¹¹ for eachoccurrence is hydrogen; each of R¹² and R¹³ independently for eachoccurrence is hydrogen or optionally substituted alkyl; R²⁴independently for each occurrence is

wherein n is 4, and each of R¹⁵ and R¹⁶ independently for eachoccurrence is hydrogen or —(C═O)NR¹²R¹³; and R²³ independently for eachoccurrence is —N(R¹³)(C═NR¹²)NR¹²R¹³.
 38. The compound of claim 37,wherein R²⁴ independently for each occurrence is


39. The compound of claim 38, wherein R²⁴ independently for eachoccurrence is


40. The compound of claim 39, wherein each occurrence of R¹³ in Formula(IIa-2) is independently optionally substituted alkyl.
 41. The compoundof claim 40, wherein R²³ independently for each occurrence is—N(H)(C═NH)NH₂.
 42. The compound of claim 37, wherein R³ is hydrogen,and R¹⁰ is alkyl.
 43. The compound of claim 37, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 44. The compound of claim37, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 45. A process ofpreparing a compound of claim 37 or a pharmaceutically acceptable saltthereof, which comprises: reacting a compound having the formula

wherein m is 1; Y is O; each of R³ and R¹⁰ is independently hydrogen oralkyl; R⁴ and R⁵ taken together with the carbon to which they are bondedform (C═O); R⁶ and R⁷ taken together form a bond; and R⁸ and R⁹ takentogether form a bond; with a compound having the formula HN(R¹¹)R²⁴,wherein R¹¹ in each occurrence is independently is hydrogen; and R²⁴ is

wherein n is 4, and each of R¹⁵ and R¹⁶ independently for eachoccurrence is hydrogen or —(C═O)NR¹²R¹³; R²³ independently for eachoccurrence is —N(R¹³)(C═NR¹²)NR¹²R¹³; and each of R¹² and R¹³independently for each occurrence is hydrogen or optionally substitutedalkyl.
 46. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to claim 37, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 47. The pharmaceutical composition of claim 46,further comprising one or more additional therapeutic agents.
 48. Amethod for treating a microbial infection in a patient in need thereof,the method comprising administering to the patient a therapeuticallyeffective amount of a compound according to claim 37, or apharmaceutically acceptable salt thereof.
 49. The method of claim 48,wherein the microbial infection is a Gram negative bacterial infectionor a Gram positive bacterial infection.
 50. The method of claim 49,wherein the Gram positive bacteria is selected from the group consistingof Streptococcus spp., Staphylococcus spp., Bacillus spp.,Carynebacterium spp., Clostridium spp., Listeria spp., and Enterococcusspp.
 51. The method of claim 50, wherein the Gram positive bacteria isStaphylococcus aureus.
 52. The method of claim 51, wherein theStaphylococcus aureus is Methicillin resistant Staphylococcus aureus.53. The method of claim 48, the method further comprising administeringone or more additional therapeutic agents.
 54. A compound of Formula(II) or a pharmaceutically acceptable salt thereof:

wherein m is 1; Y is O; B is NR¹¹R²⁴; each of R³ and R¹⁰ isindependently hydrogen or alkyl; R⁴ and R⁵ taken together with thecarbon to which they are bonded form (C═O); R⁶ and R⁷ taken togetherform a bond; R⁸ and R⁹ taken together form a bond; R¹¹ in eachoccurrence is hydrogen; R²⁴ is

wherein n is 0; each of R¹⁵ and R¹⁶ independently for each occurrence ishydrogen; and R²³ independently for each occurrence is arginine or anarginine derivative.
 55. The compound of claim 54, wherein R³ ishydrogen, and R¹⁰ is alkyl.
 56. The compound of claim 54, wherein thearginine derivative independently for each occurrence is

wherein each of R¹² and R¹³ independently for each occurrence ishydrogen or optionally substituted alkyl.
 57. The compound of claim 54,wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 58. The compound of claim54, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 59. A process ofpreparing a compound of claim 54 or a pharmaceutically salt thereof,which comprises: reacting a compound having the formula

wherein m is 1; Y is O; each of R³ and R¹⁰ is independently hydrogen oralkyl; R⁴ and R⁵ taken together with the carbon to which they are bondedform (C═O); R⁶ and R⁷ taken together form a bond; and R⁸ and R⁹ takentogether form a bond with a compound of formula HNR¹¹R²⁴, wherein R¹¹for each occurrence is hydrogen; and R²⁴ independently for eachoccurrence is R²³, wherein R²³ independently for each occurrence isarginine or an arginine derivative.
 60. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 54, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 61. The pharmaceuticalcomposition of claim 60, further comprising one or more additionaltherapeutic agents.
 62. A method for treating a microbial infection in apatient in need thereof, the method comprising administering to thepatient a therapeutically effective amount of a compound according toclaim 54, or a pharmaceutically acceptable salt thereof.
 63. The methodof claim 62, wherein the microbial infection is a Gram negativebacterial infection or a Gram positive bacterial infection.
 64. Themethod of claim 63, wherein the Gram positive bacteria is selected fromthe group consisting of Streptococcus spp., Staphylococcus spp.,Bacillus spp., Carynebacterium spp., Clostridium spp., Listeria spp.,and Enterococcus spp.
 65. The method of claim 64, wherein the Grampositive bacteria is Staphylococcus aureus.
 66. The method of claim 65,wherein the Staphylococcus aureus is Methicillin resistantStaphylococcus aureus.
 67. The method of claim 62, the method furthercomprising administering one or more additional therapeutic agents.